Garcinia mangostana L. Pericarp Extract and Its Active Compound α-Mangostin as Potential Inhibitors of Immune Checkpoint Programmed Death Ligand-1

Abstract

α-Mangostin, a major xanthone found in mangosteen (Garcinia mangostana L., Family Clusiaceae) pericarp, has been shown to exhibit anticancer effects through multiple mechanisms of action. However, its effects on immune checkpoint programmed death ligand-1 (PD-L1) have not been studied. This study investigated the effects of mangosteen pericarp extract and its active compound α-mangostin on PD-L1 by in vitro and in silico analyses. HPLC analysis showed that α-mangostin contained about 30% w/w of crude ethanol extract of mangosteen pericarp. In vitro experiments in MDA-MB-231 triple-negative breast cancer cells showed that α-mangostin and the ethanol extract significantly inhibit PD-L1 expression when treated for 72 h with 10 µM or 10 µg/mL, respectively, and partially inhibit glycosylation of PD-L1 when compared to untreated controls. In silico analysis revealed that α-mangostin effectively binds inside PD-L1 dimer pockets and that the complex was stable throughout the 100 ns simulation, suggesting that α-mangostin stabilized the dimer form that could potentially lead to degradation of PD-L1. The ADMET prediction showed that α-mangostin is lipophilic and has high plasma protein binding, suggesting its greater distribution to tissues and its ability to penetrate adipose tissue such as breast cancer. These findings suggest that α-mangostin-rich mangosteen pericarp extract could potentially be applied as a functional ingredient for cancer chemoprevention.

Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways

“…The small molecule BMS-202, with modified carbonyl to hydroxyl groups, produces two enantiomers, MS and MR, both of which disrupt PD-L1 function by targeting its dimerization [ 192 ]. Furthermore, compounds such as α-mangostin and ethanol extracts can inhibit PD-L1 glycosylation and promote its degradation by binding within the pocket of the PD-L1 dimer [ 193 ]. These findings from preclinical studies highlight the potential of designing inhibitors that target PD-L1 dimers to enhance immunotherapy efficacy.…”